Generators of short lived radionuclides are widely used in nuclear medicine, the most common of which is the Mo-99/Tc-99 m generator. Other parent-daughter radionuclides can also be used for a supply of the short lived daughter, provided the parent and daughter are easily separated and the daughter is readily converted, if necessary, to useful radiopharmaceutical preparations.
Gallium radioisotopes, in particular Ga-67, have been used extensively for imaging tumors and abscesses by gamma scintigraphy. The chemistry of ionic gallium in the body has been well studied. There has been considerable interest in the Ge-68/Ga-68 generator as a source of Ga-68. The 287 day half-life Ge-68 parent decays to the positron emitting 68 minute half-life Ga-68.
Since their development, positron-imaging devices have been used in a variety of studies employing positron-emitting radionuclides, the most advanced utilizing tomographic techniques. Gallium-68 is also well-suited for such positron tomography. The high resolving power of positron tomagraphy reduces the need for sophisticated collimators as well as a high target to non-target ratio, compared with that required for gamma scintigraphy using Ga-67.
The first isolation of Ga-68 was disclosed by G. I. Gleason, Int. J. Appl. Radiat. Isotopes, 8,90 (1960) and required that Ga-68 be separated from its parent by solvent extraction. The activity was back extracted into dilute HCl from which the injectable preparation was made. A similar type separation using acetylacetone-carbon tetrachloride for solvent extraction separation was described by Iofa et al., Radiokhimiya, 12, 796 (1970). An improved generator was described by Greene et al., Int. J. Appl. Radiat. Isotopes, 12, 62 (1961) in which the parent Ge-68 was loaded on an activated alumina column and the Ga-68 was eluted with an 0.005 M solution of ethylenediaminetetraacetic acid (EDTA), previously adjusted to pH 7 with sodium hydroxide.
Generators based upon adsorption and extraction columns, like those described by Greene et al., have been preferred over liquid generators, from which the desired daughter-radionuclide must be extracted by liquid phase separation techniques, because the column type generators are more convenient and can be operated by persons having less experience and less skill.
The preparation of Ge-68/Ga-68 adsorption and extraction generators have been described by many authors, and this adsorbant substrate type generator has been commercially available for several years. Ga-68 is eluted from it with 0.005 M EDTA solution as a Ga-68 EDTA complex. Nevertheless, for most applications it is necessary to use preparations containing Ga-68 in an ionic form. Because gallium-68 is obtained by elution of a Ge-68/Ga-68 generator with EDTA solution, the gallium is present in the eluate as gallium-EDTA chelate and must be chemically separated from the EDTA prior to its use as a label.
Thus, several disadvantages of the column type Ga-68 generators using complexing agents were set forth by Ehrhardt et al., J. Nucl. Med., 19 (8), 925-29 (1978) as follows. Elution at neutral pH over the long useful life of the generator causes difficulty in maintaining generator sterility. Secondly, Ga-68 can be produced by present generators only as the EDTA complex. Preparation of radiopharmaceuticals other than Ga-EDTA requires decomposition of the complex and removal of virtually all the EDTA in order for weaker complexing agents to bind successfully with the gallium. The decomposition of Ga-EDTA requires subsequent solvent extraction, ion exchange, or pyrolysis all of which are tedious and time-consuming when speed is essential. Furthermore, Ehrhardt et al. (ibid.) state that it is doubtful whether these methods can produce radiopharmaceuticals uncontaminated by Ga-EDTA, since even quantities of EDTA as small as 10.sup.-18 moles in competition with chelates having a stability constant of log K.perspectiveto.10 can lead to Ga-68 preparations that are .about.10% Ga-68 EDTA, due to the very high stability constant of Ga-EDTA (log K=34).
Thus, Ehrhardt et al. suggest a solvent system using a weaker complex that EDTA for recovery of Ga-68 from the germanium, and suggest extracting the Ga-68 with oxine in chloroform followed by conversion of this Ga complex to other radiopharmaceutical forms. This procedure is similar to the solvent extraction procedures of Gleason and Iofa et al., mentioned previously.
Because of the desirability of obtaining ionic forms of Ga-68 instead of complexes such as EDTA, procedures for separating Ga-68 from EDTA solutions were developed. However, it remains highly desirable to obtain the ionic Ga-68 directly from a column type generator. Seidl et al., Radiochim. Acta., 19, 196-8 (1973) describe a Ga-68 generator using hydrous zirconium oxide as the adsorbant and 0.1 N HCl for elution. However, the yield of Ga-68 was only 5%, too low to be of practical use. Higher Ga-68 yields were found with 0.1 N HNO.sub.3, but these solutions were not useful for medical preparations. Another generator using zirconium hydroxide as the adsorbant was disclosed by Malyshev et al., Radiokhimiya, 17(1), 137-40 (1975) in which the yield of Ga-68 was 35% with Ge-68 impurity from 3.times.10.sup.-2 to 6.times.10.sup.-3 %.
Another approach described by Caletka et al., J. Radioanalytical Chem., 21, 349 (1974) was to sorb GeCl.sub.4 on silica gel, and elute the Ga-68 with 8-10 N HCl. Yields were good, but the eluate required subsequent processing to remove the excess HCl.
A generator described by Kopecky et al., Int. J. Appl. Radiat. Isotopes, 24, 73-80 (1973) and Kopecky et al., Int. J. Radiat. Isotopes, 25, 263-68 (1974) using alumina and eluted with 0.1 through 0.2 N HCl yielded about 30 to 65% Ga-68. The gallium obtained from such a generator is ionic and can be made into numerous radiopharmaceuticals. The main disadvantage of this generator is that the Al.sup.+3 content of the eluate is about 10-18 ppm for a 1.5 g alumina column, and may vary considerably with the source of the alumina. Also on aging, yields of Ga-68 decrease or are variable for the HCl-alumina system.
Ga-68 generator systems using organic ion exchangers have been described by Neirinckx et al., 2nd International Symposium on Radiopharmaceuticals, The Radiopharmaceutical Science Council, Mar. 18, 1979 (Seattle, Washington). A disadvantage of such generators is that organic resins may decompose in high radiation fields.
Most of the generators described in the literature have been 0.1 .mu.Ci to a maximum of 0.3 mCi Ge-68/Ga-68. At these levels suitable organic resins might be used, but at practical levels of 1-100 mCi Ge-68, radiation effects over the life of the generator can affect the organic resins, giving degradation products in the Ga-68 eluate which may be undesirable for medical use.
Thus, a simple and efficient generator system for obtaining Ga-68 in ionic form is quite desirable and would afford significant benefit to the field of nuclear medicine.